Oral compositions for the treatment of scalp disorders

ABSTRACT

Pharmaceutical and/or cosmetic compositions for the treatment and the prevention of scalp disorders, containing as active components extracts of  Serenoa repens  and of  Vitis vinifera.

The present invention relates to pharmaceutical and/or cosmetic oralcompositions for the treatment and the prevention of disorders of thescalp, containing ingredients of vegetable origin.

More particularly, the present invention relates to pharmaceuticaland/or cosmetic oral compositions for the treatment and the preventionof disorders of the scalp, containing as active components extracts ofSerenoa repens and of Vitis vinifera.

Dandruff, seborrhea and hair loss or alopecia are among the most commondisorders of the scalp.

A number of studies have proved that androgenetic alopecia is aphysiological process in genetically predisposed individuals, althoughits very high frequency, in particular in Caucasians, makes any attemptto establish the heritability mode difficult. Although such heritabilityis strongly autosomic, the number of the involved genes has not yet beenestablished.

There is evidence of the relationship between androgens and developmentof androgenetic alopecia: for example, pattern baldness is related withreduced time in hair anagen growth phase, and androgens are known toinduce shorter anagen growth phases in scalp hair follicles, whichbecome finer and thinner. Tissue androgens, testosterone and more potentdihydrotestosterone (DHT), can reach the skin through blood circulationor can be locally produced in hair follicles and sebaceous glands byspecific enzymes in the steroid cascade. The kinetic constants of anumber of enzymes which mediate the formation of DHT, 5-alpha-reductaseincluded, in hair follicles and sebaceous glands of human hair fromscalps of man and women affected with androgenetic alopecia have beenevaluated; furthermore, androgen receptors specifically binding DHT havebeen identified in sebocytes and human hair.

Recently, binding studies showed that the dermal papilla of hairfollicles of balding subjects contains more androgen receptors than thatof normal subjects. As a consequence of this hormone pathway, abnormalsebum secretion may occur, which in turn induces further worsening ofbaldness as well as overproduction of sebum and dandruff.

Two isoforms of 5-alpha-reductase are known: type 1 and type 2. Prostatecontains the type 2 isoenzyme, whereas skin and cutaneous appendages(hair and sebaceous glands)-contain both type 1 and type 2. Finasteride,a type 2 5-alpha-reductase inhibitor originally used for the therapy ofprostate hyperplasy, revealed active also in the treatment ofandrogenetic alopecia; furthermore, a relationship between baldnessseriousness and benign prostate hyperplasy seriousness has beenobserved.

In addition to 5-alpha-reductase, also oxidative stress (pollution,atmospheric agents and the like) and poor intake of oligoelements andsulfated amino acids (such as methionine, cysteine and cystine) throughdiet adversely affect the hair.

The numerous pharmaceutical or cosmetic formulations for the treatmentof dandruff and alopecia at present commercially available have not yetsatisfactorily solved these problems.

It has now been found, and this is the object of the present invention,that pharmaceutical and/or cosmetic oral formulations containing acombination of active principles of vegetable origin induce excellentresults in the treatment of scalp disorders, in particular alopecia anddandruff, as a result of the combination of the different activities ofthe various components, which exert, inter alia, antiandrogenic,antiradicalic, antiaging activities.

The compositions of the invention act on the factors which contribute tothe development of said scalp disorders, in particular on androgens,oxidative stress, oligoelements and sulfated amino acids present in thediet.

More particularly, the present invention relates to oral pharmaceuticaland/or cosmetic compositions containing:

-   -   a) extract of Serenoa repens,    -   b) standardized extract of Vitis vinifera, in the free form        and/or as phospholipid complexes.

The components of the compositions of the present invention are allknown and used in the pharmaceutical and/or in cosmetic fields. However,it should be noted that the single components, when used separately,exert by far lower activity than that obtained with the compositions ofthe present invention, in which the various components have been foundto exert a synergistic effect of in the prevention and treatment ofscalp disorders.

-   -   a) The extract of Serenoa repens is a vegetable remedy effective        in benign prostate hyperplasy due to its antiandrogenic action.        This product contains a specific mixture of fatty acids        extracted from the plant by means of CO₂ in supercritical        conditions, as disclosed in EP 250,953, and when tested “in        vitro” on prostate isolated cells, it revealed strong affinity        to androgen receptors, as demonstrated by displacement with        radiolabelled 3H-methyltrienolone.    -   b) The extract of Vitis vinifera, disclosed in GB 1,541,469,        includes gallic acid, as well as catechin and epicatechin        monomers, dimers, trimers, tetramers, pentamers, hexamers and        heptamers in the free form or esterified as gallates. Extensive        searches proved its many properties: a) strong, complete        antioxidant profile which allow to remove the more reactive        radicals, thereby counteracting all the phenomena related to        free radicals activity; b) ability to inhibit xanthine-oxidase        and to chelate Cu⁺⁺ and Fe⁺⁺, thus preventing the enzymatic        release of free radicals into tissues; c) ability to inhibit        collagenase, hyaluronidase, elastase and beta-glucuronidase,        thus protecting blood vessels and connective tissue against the        damages caused by proteolytic enzymes released following UV        radiations, oxidative stress and during the development of the        inflammatory response.

As mentioned above, the extract of Vitis vinifera may also be present inthe form of phospholipid complexes as disclosed in U.S. Pat. No.4,963,527.

The compositions of the present invention may optionally contain, inaddition to the above stated components, further ingredients havinguseful or anyway complementary actions, for example oligoelements, suchas zinc, copper, iron, selenium, magnesium; amino acids, such asL-lysine, L-proline, L-hydroxyproline, L-leucine, L-isoleucine,L-methionine, L-cysteine, L-cystine; vitamins, such as the vitamins Bcomplex, vitamin E and vitamin C.

The compositions of the invention will be formulated in oral dosageforms, according to conventional techniques, as described, for example,in “Remington: The Science and Practice of Pharmacy”, Lippincott,Williams and Wilkins Eds, December 2000). Said compositions may be inthe form of tablets, capsules, oral preparations, powders, granules,lozenges, powders for reconstitution, injectable solutions orsuspensions, and liquids for infusions or suppositories.

Tablets and capsules for the oral administration will usually bepresented in the form of unitary dosage, and will contain conventionalexcipients such as binders, diluents, tabletting agents, lubricants,disintegrants, dyes, flavors and wetting agents. Tablets may be coatedaccording to methods well known in the art.

According to an embodiment of the invention, the compositions will bepresented in the form of two capsules for the simultaneousadministration, one containing the extracts of the invention and theother containing the oligoelements mentioned above.

The oral liquid preparations may, for example, be in the form of aqueousor oily solutions or suspensions, emulsions, syrup or elixir, or dryproducts for reconstitution with water or other suitable carrier beforeuse. Said liquid preparations may contain conventional excipients suchas suspending agents, emulsifiers, non aqueous carriers, preservatives,flavors or dyes.

The compositions of the present invention will be used in such dosageforms as to provide a components daily intake within the followingranges:

-   -   a) standardized extract of Serenoa repens (40-320 mg/day);    -   b) standardized extract of Vitis vinifera in the free form        and/or as phospholipid complexes (50-300 mg/day and 150-900 mg        day, respectively).

The oligoelements can be present in such amounts as to provide a dailyintake of 0.1 to 100 mg.

The compositions of the invention revealed effective in the treatment ofscalp disorders, with beneficial effects on trichogram, dandruff,seborrhea and baldness, and in the prevention of said disorders,ensuring healthy hair.

The results of the pharmacological tests are reported in the following.

Effect on Dandruff, Sebum Production and Hair Loss

60 subjects with dandruff (scaling of the scalp skin) were randomized infour groups. The first received with one capsule prepared according toExample 1 daily for 8 weeks. Evaluations were carried out immediatelybefore starting the treatment, at the end of the treatment (after 8weeks) and 4 weeks after interrupting the treatment (follow-up). Thesecond group received placebo under the same experimental conditions.The third and the fourth groups received 25 and 80 mg of extracts ofVitis vinifera and Serenoa repens, respectively.

The results reported in Table 1 evidence that after 8 weeks of treatmentthe number of desquamated cells (evaluated according to Mac Ginley etal. J. Invest. Dermatol. 53,107,1969) was reduced from 85 to 18cells/cm². The number of desquamated cells was still significantlyreduced after 4 weeks of follow-up (21 cells/cm²). TABLE 1 MAC GINLEYCOUNT (cells/cm2) Treatment Start 8 weeks 12 weeks Placebo 83 ± 3.7 85 ±3.1 86 ± 3.6 Capsules of Ex. 1 85 ± 2.1 18 ± 2.4 21 ± 3.1 Extract ofVitis 87 ± 2.9 75 ± 3.1 80 ± 2.7 vinifera 25 mg Extract of Serenoa 84 ±3.1 41 ± 4.3 63 ± 2.4 repens 80 mg

The results reported in Table 2 prove that the treatment with thecapsules of the invention significantly reduces the mean value of scalpsebum from 105 to 92 U.S. (U.S.=arbitrary Sebometric Units). It isparticularly remarkable that the value of sebometric units is stillsignificantly reduced (95 U.S.) even 4 weeks after the end of thetreatment. TABLE 2 SEBOMETRY (U.S.) Treatment Start 8 weeks 12 weeksPlacebo 106 ± 7.3 105 ± 9.3 106 ± 7.9 Capsules of Ex. 1 104 ± 8.1  92 ±6.4  95 ± 9.3 Extract of Vitis 107 ± 8.3 100 ± 6.6 103 ± 9.1 vinifera 25mg Extract of Serenoa 105 ± 7.9  97 ± 7.1  99 ± 8.4 repens 80 mg

The effect on hair loss was studied by trichogram evaluation, whichconsists in taking a sufficient number of hair (about 50) from thehigher and antero-nucal frontal areas of each subject (Bosse K.,Hautzart, 18, 35, 1967;

Bosse K., Hautzart, 18, 218, 1967). The percentage of hair in anagen(growth), catagen (mature), or telogen (rest) phase was evaluated bymicroscope observation of each single hair shaft under the microscope.Any dystrophic anagen condition, namely the phase in which hair haveminiaturized shaft, has also been evaluated in this study. A percentageof hair in telogen phase higher than 10-15% (considered normal) is anindex of a clinical pathologic condition of hair loss. The resultsreported in Table 3 evidence that after 8 week treatment with thecapsules of the invention, increase in hair bulbs in anagen phase,decrease in the value of dystrophic anagen hair and, as a consequence,reduction of bulbs in telogen phase were observed. These results werestill visible after 4 weeks of follow-up. It should be noted that in theplacebo group the clinical situation both at the end of the treatmentand after the 4 weeks of follow-up was diametrically opposed. TABLE 3EFFECT ON HAIR LOSS PLACEBO CAPSULES of EX. 1 Start Anagen 82% Anagen80% Catagen 1% Catagen 1% Telogen 17% Telogen 19% Dystrophic anagen 23%Dystrophic anagen 20% After 8 weeks Anagen 81% Anagen 82% of treatmentCatagen 2% Catagen 1% Telogen 17% Telogen 17% Dystrophic anagen 22%Dystrophic anagen 16% After 12 weeks Anagen 80% Anagen 83% (4 weeksuspension) Catagen 1% Catagen 1% Telogen 19% Telogen 16% Dystrophicanagen 24% Dystrophic anagen 17%

Effect on Seborrheic Dermatitis

40 subjects affected with seborrheic dermatitis of the scalp wererandomized in two groups. The first group received a capsule preparedaccording to Example 1 daily for 8 weeks. Instrumental sebometricevaluation was carried out immediately before starting treatment, at theend of treatment (after 8 weeks), and 4 weeks after suspension oftreatment (follow-up). The second group received placebo under the sameexperimental conditions. The third and fourth groups received 25 and 80mg of extracts of Vitis vinifera and Serenoa repens, respectively.

The results reported in Table 4 clearly show that treatment with thecapsules of the invention significantly reduced scalp sebum mean valuein subjects with seborrheic dermatitis, whose sebum values are above 200U.S. (U.S.=arbitrary Sebometric Units). This value is stillsignificantly low after 4 weeks of follow-up. TABLE 4 SEBOMETRY (U.S.)Treatment Start 8 weeks 12 weeks Placebo 233 ± 13 210 ± 16 240 ± 15Capsules of Ex. 1 241 ± 14 135 ± 9  150 ± 12 Extract of Vitis 227 ± 9 209 ± 14 220 ± 13 vinifera 25 mg Extract of Serenoa 231 ± 13 200 ± 16203 ± 16 repens 80 mg

Examples of the compositions according to the invention are reported inthe following.

EXAMPLE 1 Hard-Gelatin Capsules

Each 326 mg capsule contains: Extract of Serenca repens 50.0 mg Extractof Vitis vinifera extract 25.0 mg L-cysteine 30.0 mg L-histidine 30.0 mgL-methionine 30.0 mg D-calcium pantotenate 15.0 mg Zinc citrate(equivalent to 3 mg of zinc) 10.0 mg Copper citrate (equivalent to 0.8mg of copper)  2.3 mg Beta-carotene 10% W.S.  4.3 mg (equivalent to 700U.I. of vitamin A) Colloidal silica 30.0 mg (Aerosil 200 - DEGUSSA)Microcrystalline cellulose 30.0 mg (Avicel PH 101 - FMC) Maltodextrin30.0 mg (Lycatab DSH - ROQUETTE) Pregelatinized starch 21.9 mg (AmidoSTA 1500 - COLORCON) Cross-linked sodium carboxymethylcellulose 15.0 mg(Ac-Of-Sol - FMC) Magnesium stearate  2.5 mg

EXAMPLE 2 Hard-Gelatin Capsules

Each 326 mg capsule contains: Extract of Serenoa repens  80.0 mg Extractof Vitis vinifera  25.0 mg Soy polysaccharides  83.0 mg (Emcosoy -MENDELL) D-calcium pantotenate  15.0 mg Zinc gluconate (equivalent to 3mg of zinc) 23.84 mg Copper gluconate (equivalent to 0.8 mg of copper) 5.7 mg Colloidal silica  6.2 mg (aerosil 200 - DEGUSSA)Microcrystalline cellulose  30.0 mg (Avicel PH101 - FMC) Pregelatinizedstarch  72.0 mg (STA1500 starch - COLORCORN) Magnesium stearate  2.5 mg

1. The use of: a) extract of Serenoa repens; b) extract of Vitisvinifera in the free form and/or as phospholipid complexes; for thepreparation of oral pharmaceutical and/or cosmetic compositions for thetreatment and the prevention of scalp disorders.
 2. The use of: a)extract of Serenoa repens; b) extract of Vitis vinifera in the free formand/or as complexes with phospholipids; in combination with additionalactive ingredients selected from the group consisting of oligoelements,such as zinc, copper, iron, selenium, magnesium; amino acids, such asL-lysine, L-proline, L-hydroxyproline, L-leucine, L-isoleucine,L-methionine, L-cysteine, L-cystine; vitamins, such as the vitamins Bcomplex, vitamin E and vitamin C, for the preparation of oralpharmaceutical and/or cosmetic compositions for the treatment and theprevention of scalp disorders. 3.-11. (cancelled)